Abstract Multiple sclerosis (MS) is an incurable, chronic disease of the CNS that arises in young adulthood and precipitates severe disability by middle age. In MS, immune cells attack myelin in the CNS, leading to neuronal damage and loss of functionality. Currently available therapeutics are marred by incomplete efficacy and severe side effects, so there is significant need to develop novel interventions for MS. An emerging field that holds promise for the modulation of immune function as well as neuroprotection is therapy targeting the endoplasmic reticulum (ER). Indeed, recent works have demonstrated that the ER is just not a protein synthesis and secretory organelle, but a central signaling hub. Our proposal is centered on sigma-1 receptor (S1R), an ER-resident protein that makes an attractive novel MS drug target due to the fact that numerous S1R ligands are already in clinical use and are well tolerated, even with chronic dosing schedules. S1R ligands have been reported to possess neuroprotective properties, making them potentially able to halt the damage that occurs inevitably in MS, even with currently available treatments. We aim to expand the appreciated role of S1R beyond neuronal function. Our central hypothesis is that S1R is a key regulator of inflammation that acts through ER signaling. Guided by strong preliminary evidence, this hypothesis will be addressed by pursuing two specific aims: 1) Characterize inflammatory signaling in myeloid cells and CD4+ T cells lacking S1R and 2) Investigate effect of S1R expression on EAE severity. In the first aim, we will investigate the contribution of S1R to the inflammatory response of myeloid cells and T cells, which are two main cell types involved in MS pathology progression. We will also undertake mechanistic studies to understand how S1R influences the function of two central cell types in MS, helper T cells, macrophages and microglia, which will potentially reveal additional novel therapeutic approaches. In the second aim, we will test whether the deletion S1R affect the progression of experimental autoimmune encephalomyelitis and the cellular compartment relying the most on S1R function during EAE. The proposed research is significant and innovative because it will test whether S1R represents a novel target for therapy development for patients with MS. Furthermore, the insights gained from our studies will lead to fundamental advances in understanding how the ER and S1R can influence inflammatory responses in MS and beyond.